Project Summary/Abstract: Childhood brain cancer is the most common solid tumor in children affecting approximately 2,500 children a year with an estimated 22,000 children living in the United States with a malignant brain tumor, which establishes this as an orphan disease. Current therapies for malignant childhood brain tumors including surgery, chemotherapy and radiation are very damaging to the developing brain of a child and can result in significant long-term disabilities such as cognitive difficulties, neuroendocrine dysfunction, and neurosensory deficits in survivors. Approximately 30-40% of children with malignant brain cancer do not survive, and high-grade tumors that recur after current therapies are uniformly fatal. Therefore, novel therapies which target tumor cells while sparing normal cells and stimulate an anti-tumor immune response are desperately needed. Oncolytic engineered herpes simplex virus (oHSV) therapy offers an inventive, targeted, less-toxic approach for children with incurable brain tumors and may afford an improved margin of safety as an adjuvant therapy for curable tumors allowing for lower doses and less toxicity from traditional therapies. HSV has been successfully engineered to introduce mutations in the virus (e.g. ?134.5 neurovirulence gene) that prevent infection in normal brain cells while maintaining the virus? ability to kill cancer cells and stimulate an anti-tumor immune response. UAB conducted 3 Phase I trials of oHSV G207, which has both copies of ?134.5 deleted and an insertional deletion of the ribonucleotide reductase gene for added safety, given alone and with a single small dose of radiation to enhance virus replication and an anti-tumor immune response, in adults with recurrent high- grade glioma. These trials conclusively demonstrated safety of G207 inoculated intratumorally or in surrounding brain tissue, and ?half of patients had radiographic evidence of tumor response, including two long-term survivors (>5.5 years). An active pediatric trial of G207 in supratentorial brain tumors has demonstrated safety of G207 alone with evidence of responses to G207 in 7 of 8 patients including a patient >21months post-G207 with an ongoing response without any additional therapies. These trial data coupled with our preclinical data demonstrating that aggressive pediatric brain tumors are highly sensitive to G207 and the lack of available therapies for patients strongly support an oHSV trial for children with progressive malignant cerebellar tumors. We propose to conduct a Phase I clinical trial of G207 alone and combined with a single low dose of radiation in children with recurrent cerebellar brain tumors. We hypothesize that G207 will be safe and tolerable with evidence of efficacy in children with refractory cerebellar malignancies. Our primary goal is to determine safety. Our secondary aims are to obtain preliminary information on the effectiveness of and immune response to G207 and on tumor genotypic and phenotypic features which may predict a response to oHSV. Importantly, this trial will support the clinical development of G207 for use in this devastating orphan disease.